The fact that cleavage of single peptide linkages in proteins often leads to extensive conformational alteration, including regions far removed from the cleavage site is not fully understood. We propose, based on the work of Linderstrom-Lang and Schellman, that disruption primarily occurs within protein structural domains that are stabilized by cooperative interactions and that cleavage of single peptide linkages of the domain perturbs the entire cooperative interaction. We name this domain the Linderstrom-Lang-Schellman (LS) domain. Here, peptide bonds of proteins permissble for cleavage with retention of the native conformation that were found first with riboneclease A by F. Richards are defined not to be a part of the LS domain. To gain insight into the structure of the LS domain, the nature of the cooperative interaction and the magnitude of the contribution of the cooperative interacton to unfolding free energy of proteins, I reviewed experimental observations: on fragment complexation (ribonuclease A, staphylococcal nuclease and cytochrome c), destabilized N-terminal large fragments (ribonuclease A and nuclease), cooperative folding and stabilization of proteins (ribonuclease A, nuclease and cytochrome c), the close relationship of the three-dimensional structure between fragment complexes and the original protein (ribonuclease A and nuclease), ligand induced stabilization (nuclease), 3D domain swapping defined by D. Eisenberg and colleague, circular permutation invented by H. Schachman and colleague (dihydrofolate reductase), evolutionary conservation (the cytochrome fold defined by R. Dickerson and colleague). The LS domain model fits these diverse observations. Such a consistency supports the model. Based on analysis of these observations the cooperative interaction of the LS domain is important for the mechanism of 3D domain swapping as well as for stabilization and thereby, determination of the ground state of native proteins. We conclude that proteins fold into the structure in which the cooperative interaction of the LS domain stabilzes the structure. This would occur whichever folding pathway may be followed. If the cooperative interaction of the LS domain were disrupted, the conformation of proteins would be an ensemble of partly folded population and disordered population. Furthermore, analysis of the observations reveals that the LS domain generally contains a hydrophobic core. Further, based on studies of cytochrome c and the Tsao, Evans and Wennerstrom model of electrostatic interactions between two hydrophobic monolayers, we propose the model that the hydrophobic core of the LS domain is polarizable and responds to the surface charges through its polarizability to stabilize the LS domain and therefore, the protein, explaining in part the nature of the cooperative interaction. In 3D domain swapped dimers permissible peptide bonds for cleavage of proteins are located in the hinge loop (open interface) of the dimer so that the cooperative interaction of the LS domain is reestablished in each of the two domains of the dimer (each of the two close interfaces of the dimer is a part of the LS domain). That is, each of the two domains of the dimer is stabilized by the cooperative interaction of the LS domain. Thus, 3D domain swapping is inherent of proteins whose ground state is stabilized by the cooperative interaction of the LS domain. An increasing number of proteins are shown to have their function regulated by 3D domain swapping. Understanding the nature of the cooperative interaction of the LS domain such as proposed polarizability is important not only for fuller understanding of protein folding or protein engineering but also for understanding physiological as well as pathological cellular processes involving 3D domain swapping.